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Abramson Family Cancer Research Institute
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Reduction of Breast or Ovarian Cancer Risk by Prophylactic Surgery in BRCA1 or BRCA2 Mutation Carriers Author: Timothy R. Rebbeck, Ph.D.
Affiliation: Assistant Professor of Epidemiology
in Biostatistics and Epidemiology,
University of Pennsylvania
Posted Date: April 19, 1998
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Last Revision Date: Sunday, 14-Feb-1999 13:54:27 EST
Copyright © 1994-1999, The Trustees of the University of Pennsylvania
IntroductionThe availability of genetic testing for inherited mutations in the BRCA1 and BRCA2 genes provides potentially valuable information to women at high risk of breast or ovarian cancer. Unfortunately, women at extremely high risk of breast or ovarian cancer, including carriers of inherited mutations in BRCA1 or BRCA2, have relatively few clinical management options available to reduce their cancer risk. One option is increased surveillance (e.g., through mammography, clinical examination, and self-examination). Many high-risk women also consider the option of prophylactic mastectomy (PM) or prophylactic oophorectomy (PO), in the hope that removal of healthy breast or ovarian tissue will reduce their risk of developing invasive malignancy. Unfortunately, no studies have been conducted to date that evaluate the value of PM/PO in women known to be at high risk of developing breast or ovarian cancer because of the inheritance of a BRCA1/BRCA2 mutation. Therefore, recommendations for (or against) the use of PM and/or PO have not been based on data obtained from women with a defined increased risk, such as women who carry an inherited BRCA1 or BRCA2 mutation. This article raises issues that women should consider as they decide whether or not to undergo prophylactic surgery. For both PM and PO, similar questions arise:
PART I. PROPHYLACTIC MASTECTOMY (PM)Question 1: To what degree is the risk to develop or die from disease reduced by these surgical options? Cancer risk is not completely eliminated by PM. The underlying motivation for PM as a cancer prevention strategy is that removal of breast or ovarian tissue that may become malignant should reduce subsequent cancer risk. However, it is clear that PM cannot completely prevent the subsequent development of breast cancer, since patients have developed breast or ovarian cancer subsequent to PM. Therefore, a woman should be aware that PM does not prevent all breast cancer. At best, PM may reduce risk of developing breast cancer. The reason for residual breast cancer risk is that the available PM surgical procedures do not remove 100% of "at risk" tissue. Residual breast tissue has been found even after total mastectomy, which suggests that removal of a greater amount of tissue may be required to achieve optimal protection. It has been estimated that 5-10% of breast tissue remains after subcutaneous PM, and this residual tissue presumably has the same potential to become cancerous as the tissue that was removed. Thus, incomplete risk reduction could be explained by residual tissue left after PM. It could be hypothesized that the relatively smaller amount of residual tissue may correspond to a relatively smaller cancer risk, but no study has evaluated whether this is the case in women who carry a germline mutation in BRCA1 or BRCA2. In addition, it is possible that the detection of breast tumors in this residual tissue may be more difficult my mammography due to its anatomical location. Risk reduction estimates have not been made in women with defined cancer risk. As suggested above, PM and PO may not prevent all cancer, but may reduce cancer risk. The question that women who are considering this surgery need to know is how much risk reduction will they have by undergoing this surgery. Unfortunately, there is little data that may help to answer this question in very high-risk women (including BRCA1/BRCA2 mutation carriers). Two large studies addressing this topic are described below:
Unfortunately, these studies have been conducted in women who represent a heterogeneous group with respect to breast cancer risk, and it can be argued that these estimates are not meaningful to women who are truly at high risk. The number of subsequent cancers reported here may be much lower than in a BRCA1 or BRCA2 mutation carrier population if their baseline cancer risk was relatively low. No study of PM has been undertaken in women whose elevated cancer risk has been based on knowledge of inherited mutations or pedigree analysis. Therefore, there is no accurate estimate of risk reduction associated with PM that is valid for women with a BRCA1 or BRCA2 mutation. It is also important to note that even in women with defined BRCA1 or BRCA2 mutations, cancer risk may vary substantially. First, the site of cancer may vary by location of the mutation within BRCA1 or BRCA2. In addition, women with BRCA1 mutations may have a higher ovarian cancer risk than women with BRCA2 mutations. Thus, knowledge about the actual BRCA1 or BRCA2 mutation might be considered when evaluating the use of PM. In addition, some information is now becoming available that other risk factors (such as reproductive history) and other genes may modify cancer risk (Rebbeck et al. 1998). This information may also help inform risk estimation, and aid in the decision about use of PM. Studies have not considered mortality from cancer. If we assume that cancer risk is reduced by prophylactic surgery, It makes sense that if fewer tumors develop, then a woman is less likely to die of disease. However, in deciding whether to operate or not, women should be aware that almost no information is available about risk of death after PM. For example, if tumors that arise out of residual tissue are less easily detectable at an early stage, they may have the potential to be more lethal than those that are detectable at an early stage. Similarly, reconstructive surgery and potential for scar tissue formation may make the detection of tumors more difficult, possibly resulting in a later stage at detection and poorer prognosis. Therefore, potential for mortality from breast cancer may still exist after surgery. In addition, a false sense of security may arise in patients who have undergone PM. It is crucial that women continue to pursue screening (e.g., clinical breast exam or mammography) following PM to avoid being diagnosed with late-stage tumors with poor prognosis. Question 2: What is the relationship of surgery to other preventive measures? The relationship between surgery and other prevention strategies is not well understood. In addition to PM, women at increased breast cancer risk due to a BRCA1 or BRCA2 mutation should consider alternative cancer prevention options. These include close surveillance by breast self-exam, clinical breast exam, and mammography. Recommendations for enhanced levels of screening have been made by many groups, but generally include; beginning breast screening at an earlier age (e.g., 10 years prior to the age at which the earliest breast cancer was diagnosed in the family), and more frequently (e.g., mammography and clinical breast exam every six months). Concerns about intensive screening include limited ability to detect cancers by mammography in younger women. Other screening methods, such as breast imaging by MRI, are being tested, but are also not widely available outside of research protocols. Debra Schrag and her colleagues at The Dana Farber Cancer Institute have suggested that additional gain of lifespan may be achieved in BRCA1 or BRCA2 carriers who undergo PM (2.9-5.3 years), even after the use of other screening measures was considered. However, these analyses made numerous assumptions that cannot yet be verified in BRCA1 or BRCA2 mutation carriers, and some important competing factors (use of hormone replacement therapy, clinical/self breast exam use, mammography use) were not completely considered in these analyses. Question 3: What is the optimal type and timing of surgery? The optima l type of surgical procedure for breast cancer prevention is not established. As with any surgical procedure, risks of morbidity and mortality exist from the prophylactic surgeries themselves. However, it is unlikely that surgical risks will vary by mutation status, so that the standard population estimates of complications from prophylactic surgery should be applicable. More importantly, it is not clear what type of surgical procedure is optimal for breast cancer prevention. The studies of PM to date have primarily used subcutaneous mastectomy as the surgical method. However, there are no direct comparisons that suggest what type of surgery (e.g., subcutaneous vs total PM) may be most effective in reducing risk. Subcutaneous PM may leave a larger amount of residual breast tissue behind, but no study has evaluated whether this translates into a greater post-PM breast cancer risk. Nonetheless, some clinicians do not recommend subcutaneous PM as a prophylactic procedure in high-risk women. Since there are major cosmetic differences (and therefore potential differences in post-PM quality of life) between different types of surgery, it will be important to determine whether there are differences in risk reduction due to different surgical approaches. Proper timing of surgery is poorly understood. Cancers tend to arise in BRCA1 or BRCA2 mutation carriers at a substantially earlier age than in the general population. Breast cancers have been (rarely) reported in women under the age of 25, although the median age of BRCA1- and BRCA2-associated tumors is substantially later -- approximately 40 years of age. Thus, there is little justification for PM at a very early age (e.g., before age 25). However, cancer risk (including age of cancer onset) may vary according to BRCA1 or BRCA2 mutation type and other factors that remain largely uncharacterized. Thus the timing of surgery is an important issue in high-risk women which remains unresolved. Question 4: How can the potential benefits of surgery be weighed against possible negative emotional, economic, or social costs of surgery? Psychosocial concerns about PM are poorly understood. Most women who are high risk need to balance the reduction in cancer risk against the financial, emotional, and social cost of PM, and against the protection they may receive by relying on cancer screening methods such as clinical breast exam or mammography. A potentially dangerous consequence of PM is that women have a false sense of security following surgery, and do not continue with cancer screening. However, these issues have not been studied in women with defined breast cancer risks. Michael Stefanek and his colleagues at Johns Hopkins have reported that women with a family history of breast cancer who actually chose to undergo PM following counseling had a greater perception of their risk, more frequently practiced breast self exam, and had higher worry scores than women who did not undergo PM. Caryn Lerman and her colleagues at Georgetown University have suggested that among women who have undergone appropriate genetic counseling and are members of families carrying a BRCA1 or BRCA2 mutation, 31% were considering PM at 1-month following counseling, while only 1% had actually undergone this surgery 6 months later. Stefanek reported that of 136 women at increased risk of breast cancer (who were not necessarily BRCA1/BRCA2 mutation carriers or from families with mutations), 10% underwent PM following counseling, 47% expressed an interest in PM but did not undergo surgery, and 43% were not interested in PM. All of those who underwent surgery reported that they were satisfied with their decision to have surgery, the degree of discomfort from surgery, their support system, and the time it took to recover from surgery. This suggests that the use of surgery as a preventive option may be low, but the reasons for this low rate of usage are unclear. Among the choices faced by a woman are the type of surgery and the use of reconstruction to enhance physical appearance. However, there is very little known about the impact prophylactic surgery has on women from a psychosocial perspective. Stefanek reported that of 14 women who underwent PM, three chose not to undergo reconstruction, and three were dissatisfied with the procedure, including two who required implant removal because of tissue rejection and infection.
PART II. PROPHYLACTIC OOPHORECTOMY (PO)Question 1: To what degree is the risk to develop or die from disease reduced by these surgical options? Cancer risk is not completely eliminated by PO. Screening and early detection of ovarian cancers is substantially more difficult than for breast cancer. Thus, the majority of tumors are diagnosed at stage III and IV disease, and mortality from later stage ovarian cancers is high. Therefore, the use of PO to reduce risk may be a more attractive option to some women than PM. However, as with PM, reports have been made indicating that intraabdominal (peritoneal) carcinomatosis (histopathologically consistent with ovarian cancer in origin) may occur in women who have undergone PO. While the origins of these cancers are poorly understood, it is hypothesized that either 1) ovarian cells remain in the peritoneum after removal of ovaries, and/or 2) ovarian tissue had some "field effect" on the surrounding peritoneum that allowed non-ovarian tissue to become malignant. These processes are poorly understood. Therefore, a woman should be aware that PO does not prevent all ovarian cancers. At best, these interventions may reduce risk of developing ovarian cancer. Risk reduction estimates have not been made in women with defined cancer risk. As with PM, removal of healthy ovarian tissue presumably reduces risk of ovarian cancer because less susceptible tissue is available to become cancerous. Removal of ovarian tissue also alters womenÆs hormone levels, inducing menopause. As a result, breast cancer risk may be lowered in addition to ovarian cancer risk. However, the magnitude of change in breast cancer risk is not known. Only two studies to date have estimated risk reduction subsequent to PO in women who may be at elevated ovarian cancer risk due to family history: The study of Struewing et al. suggest that PO high risk women may confer a 50% reduction in risk, but this risk to PO subjects is still substantially higher than that in the general population. Note that this study had too few patient-years of follow-up to reach statistical significance. Piver et al. also described 6 cases of post-PO intra-abdominal carcinomatosis following PO, but these subjects were drawn from a registry sample that was not limited to subjects whose risk may approach that of a BRCA1/BRCA2 mutation carrier (i.e., the subjects included some with only a single relative with ovarian cancer). As described above for PM, risk may vary substantially by BRCA1 or BRCA2 mutation, which in turn may affect decisions about the use of PO. Question 2: What is the relationship of surgery to other preventive measures? The relationship between surgery and other prevention strategies is not well understood. Most high-risk women need to balance the costs of PO against other screening methods such as vaginal ultrasound or CA-125 measurement. Neither of these screening options has been shown to reduce morbidity or mortality from ovarian cancer. So, women at increased risk do not have an effective alternative for ovarian cancer prevention Schrag and her colleagues have suggested that additional gain of lifespan may be achieved in BRCA1 or BRCA2 carriers who undergo PO (0.3-1.7 years). However, these analyses made numerous assumptions that cannot yet be verified in BRCA1 or BRCA2 mutation carriers, and some important competing factors (use of hormone replacement therapy, use of CA-125 or other screening tools) were not completely considered in these analyses. One study has also suggested that PO may reduce risk of breast cancer, even when low-dose estrogen replacement therapy (ERT) is used. However, these estimates were not made in women at high risk for breast or ovarian cancer, so it is not reasonable to extrapolate these findings to BRCA1/BRCA2 mutation carriers. In addition, complications from premature menopause after PO without ERT (e.g., cardiovascular disease, osteoporosis) should be weighed against the possible increase in breast cancer risk. Oral contraceptive use has also been suggested as a means of reducing ovarian cancer risk among high-risk women, but this use may increase breast cancer risk. Thus, the use of oral contraceptives in BRCA1/BRCA2 mutation carriers is unresolved. Question 3: What is the optimal type and timing of surgery? Surgery is not risk-free. Risks of morbidity and mortality exist from PO, and may vary depending on the type of procedure (e.g., laparotomy vs. laparoscopy). However, the relative risks of one surgical type or another are unlikely to be related to cancer risk, so the choice of surgery can be at the discretion of the patient and surgeon. In addition, there may be health consequences following surgery. For example, women with PO undergo "surgical" menopause, including all of its associated symptoms. Estrogen replacement therapy (ERT) may not be indicated after PO and hysterectomy to diminish these symptoms, since it may affect risk of breast cancer (see above). In addition, risks of osteoporosis, coronary artery disease, and other events associated with hormone metabolism and menopause may be influenced by surgical menopause. However, it may be an option for pre-menopausal women, since the benefits of hormone therapy for protection against osteoporosis, cardiovascular disease, etc., may outweigh any associated cancer risks. Furthermore, estrogen supplementation in premenopausal women may not increase breast cancer risk. With the availability of newer synthetic hormone replacement compounds such as raloxifen, which may confer cardiovascular and osteoporosis protection with no associated increase in breast cancer risk. Proper timing of surgery is poorly understood. Ovarian cancers in BRCA1 or BRCA2 mutation carriers have been reported in very young women, although the median age of BRCA1- and BRCA2-associated ovarian tumors is approximately 50. Thus, ovarian tumors tend to arise later than breast tumors in BRCA1/BRCA2 mutation carriers, and the timing of PO may be affected by events such as reproduction. For example, some clinicians suggest that PO may be appropriate in very high-risk women after child-bearing is complete. Schrag and colleagues have suggested that a delay of PO for 10 years in a 30-year old woman may not result in a substantial change in life expectancy. However, these analyses made numerous assumptions that cannot yet be verified in BRCA1 or BRCA2 mutation carriers, and some important competing factors (use of other screening methods or hormone replacements) were not completely considered in these analyses. Thus, the ability to balance benefit from surgery and risk or mortality reduction is not understood at this time. As discussed above, the relative benefit of PO on breast cancer risk should also be weighed in deciding on the timing of surgery. Question 4: How can the potential benefits of surgery be weighed against possible negative emotional, economic, or social costs of surgery? Psychosocial concerns about PO are poorly understood. Very little is known about the impact prophylactic surgery has on women from a psychosocial perspective. Caryn Lerman and colleagues have reported that among women who have undergone appropriate genetic counseling and are members of families carrying a BRCA1 or BRCA2 mutation, 48% were considering PO at 1-month following counseling, while only 2% had actually undergone this surgery 6 months later. This suggests that the use of surgery as a preventive option may be low, but the reasons for this low rate of usage are unclear. Clearly, the removal of breast tissue can have a profound effect on a womanÆs body image. This concern may also be relevant after PO. Removal of ovarian tissue at an early age induces menopause, which also may affect a womanÆs lifestyle in addition to health effects (see above). A potentially dangerous consequence of PO might be that women have a false sense of security following surgery, and do not continue with cancer screening. However, since no current ovarian cancer screening modality is thought to be effective at preventing ovarian cancer morbidity or mortality, the use of existing screening practices may not be helpful. Finally, insurance may not pay for the cost of this surgery, and there is concern that revealing information about cancer risk status to insurance providers may result in policy cancellation or rate increases. To date, there is little evidence that BRCA1 or BRCA2 mutation carriers will be denied coverage for PO. SummaryIt is plausible that PM and/or PO reduce breast and ovarian cancer risks in BRCA1 or BRCA2 mutation carriers. However, this knowledge is based entirely on studies conducted in women without known BRCA1/BRCA2 mutations. Therefore, it is impossible at this time to estimate the magnitude of this potential risk reduction. Carriers of BRCA1/BRCA2 mutations may wish to consider both PM and PO in cancer risk reduction. This decision should include knowledge about the competing risks and benefits of each procedure. Ideally, these decisions can be made in the context of a high-risk cancer genetic counseling program, in addition to surgical consultation, before these decisions are reached. Definitions
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